1- Background
The term diabetes means “running through”; characteristic features are excess water intake (polydipsia) and water loss (polyuria). Mellitus is Latin for honey (i.e., sweet). In a classic sense, diabetes mellitus is not a single disease because it has no single definable and distinct etiology.
The major pathophysiological abnormalities generated by diabetes mellitus include the following: (i) glucose intolerance or inappropriately high blood glucose levels in the presence of elevated or normal insulin concentrations; (ii) acidosis and ketosis; (iii) reduction of the enzymes for gluconeogenesis; (iv) reduced growth; and (v) a microangiopathy, including a thickened basement membrane of capillaries in muscle and retinal blood vessels and of the capillaries of the renal glomerulus.
Diabetes mellitus and type 1 diabetes, or more usually just diabetes, are the most common diseases associated with the pancreatic islets. Of the 313 million residents in the USA in 2011, 25.8 million children and adults or 8.3% had diabetes. Of this cohort, 18.8 million adults and children were formally diagnosed, whereas 7.0 million people were undiagnosed. For per sons under 20 years of age, 216,000 or 0.26% in this age group have diabetes. The sex distribution for individuals that were diagnosed with diabetes is that 11.8 million (49%) were men and 12.6 million (51%) were women. Each year approximately 200,000 individuals in the USA are newly diagnosed as diabetic. The life time risk in the USA for being diagnosed with diabetes if you were born after 2000 is 33% for males and 38% for females; for Hispanic Americans the risk is 50%. Diabetes is the eighth leading health-related cause of death in the United States.
Clinically there are two general classifications of diabetes: (i) type 1 or insulin-dependent diabetes mellitus (T1DM), which was formerly designated juvenile-onset diabetes; and (ii) type 2 or insulin-independent diabetes mellitus (T2DM), which was formerly designated as maturity-onset diabetes.
2- Type 1 Diabetes Mellitus or T1DM It is clear that in T1DM diabetes, the β-cells in the islet are partially or totally destroyed by an aggressive autoimmune process which is mediated by CD4+ and CD8+ cells. The end result is that there is no endogenous insulin secretion. This is determined both by the absence of plasma levels of insulin’s C peptide and the presence of an absolute daily requirement of a drug form of insulin for the maintenance of life. Individuals with T1DM are highly prone to develop metabolic ketosis, and in the untreated state there are the acute symptoms of polyuria, polydipsia, weight loss, and fatigue, all of which are secondary to the absence of insulin. Patients with T1DM require mandatory daily treatment with some form of drug insulin preparation.
Figure 1 illustrates a timeline of the etiology of type 1 diabetes mellitus that has three chapters. The first is the possible contributions of genetic predispositions (father and mother genes). Also there can be maternal contributions during pregnancy that cannot be avoided. This is followed by the chapter of the prediabetes phase; the length of this time interval can vary widely. Type 1 diabetes is known to occur in genetically predisposed individuals as a consequence of toxic environmental or infectious insult to the pancreatic β-cells coupled with the actions of an aggressive immune system that gradually, but persistently, destroys the β-cells. During this phase there is onset of the loss of functional β-cells. When the β-cell loss approaches 80%, then the pace of appearance of clinical diagnostics increases which results in a formal clinical diagnosis of T1DM.
Fig1. Timeline for onset of type 1 diabetes mellitus. T1DM is linked to several autoimmune abnormalities which aggressively carry out the selective destruction of the pancreatic islet β-cells. There are three phases that define the appearance of T1DM: they are (i) fetal life where the new genome (father’s+mother’s contributions) begins to be expressed as well as some exposure to the mother’s immune system; (ii) the prediabetes phase which may last months to years with exposure to the environment and triggering factors which leads ultimately to development of β-cell malfunction; and (iii) followed eventually by clinical diagnosis of T1DM. At some point the initiation of β-cell attrition will begin and when it becomes severe enough (loss of ~80% of the pancreas β-cells), some of the classical T1DM symptoms [polyuria (excessive production of urine), polydipsia (the desire to drink), and polyphagia (excessive eating)] will begin to appear, which facilitates the formal clinical diagnosis of T1DM.
3. Type 2 Diabetes or T2DM
Type 2 diabetes, also known as T2DM or maturity-onset diabetes, is a form of diabetes mellitus in which there is only a relative lack of insulin. It is frequently not diagnosed until after the individual is age 40. In this form of the disease, the diabetes is stated to be insulin-independent since the patient will not develop ketosis without insulin therapy. Type 2 diabetics may require only intermittent adjunctive insulin therapy, usually to manage fasting hyperglycemia. In many sub jects, adequate glucose and fuel metabolite homeostasis can be achieved by careful dietary management of nutritional and caloric intake.
The most commonly associated physical finding with maturity-onset diabetes is obesity; see Figure 2. Obesity can be defined as an enlargement of the adipose depot and is usually associated with some kind of pancreatic dysfunction. The extent of obesity can be classified by the body mass index (BMI). The equation for determination of body mass index is:
Body Mass Index = BMI = [Weight(kilograms)] / [Height (centimeters))]2
Fig2. Overweight older subjects with type 2 diabetes mellitus have a spectrum of associated medical problems. In overweight older subjects with T2DM typically their life expectancy will be 10 years shorter. About 60% of the reduced life expectancy is linked to blood vessel diseases such as heart attacks and strokes. In the extreme, diabetic older women tend to experience mental and physical disabilities and to have higher rates of premature death. Also women with T2DM have an increase in problems that are associated with the aging process, such as harmful falls, urinary incontinence, osteoarthritis, cataracts, and pulmonary disease, to name a few.
The BMI range for a normal healthy adult is 18–25. The BMI values for the following eight categories are shown in parentheses: Very severely underweight (<15) , severely underweight (15–16), underweight (16–18.5), normal weight (18.5–25), overweight (25–30), moderately obese (30–35), severely obese (35–40) and very severely obese (>40). In the interval of 1980– 2002 the prevalence of obesity doubled.
Type 2 diabetes has three metabolic abnormalities that co-occur to create a hyperglycemic state with an unusually high blood glucose concentration that can, in some instances, be greater than 200 mg/100 mL. [See Table 1 for a summary of the range of blood glucose levels.] The three abnormalities are as follows: (i) the liver’s basal level of glucose production is significantly increased; (ii) healthy skeletal muscle tissue (in the absence of type 2 diabetes) normally takes up 70–80% of all blood glucose, but in the presence of type 2 diabetes, muscle is resistant to significant glucose uptake; and (iii) in D2DM the pancreas has a decreased β-cell function which then stimulates the secretion of glucagon.
Table1. Effects of Altered Blood Glucose Levels on Several Constituents of the Blood and Urine
Treatment of type 2 diabetes mellitus with significant obesity is complex, to say the least. There are a host of concurrent diseases that can occur in T2DM; they are hypertension, coronary artery disease, dyslipidemia, congestive heart failure, and stroke.
For the population of hyperglycemic subjects older than 20 years, at least 90% are more than 10% over weight. Frequently after weight loss these individuals may regain a normal state of carbohydrate metabolism. A significant fact related to insulin-independent diabetes associated with or without obesity is that there is an apparent decrease in the sensitivity of the peripheral tissues to insulin. As a result, obese individuals have an elevated level of insulin secretion.
From the perspective of the insulin receptor present in the various target tissues, it should be emphasized that in the obese form of diabetes, characterized by glucose intolerance, hyperinsulinemia, and resistance to both endogenous and exogenous insulin, there is no evidence for a “nonfunctional form” of the insulin. The circulating ratio of proinsulin to insulin is normal; both cross-react normally in radioimmunoassays for insulin. The defect appears to be both in the number of receptors present in the target cells and in postreceptor events.
The pathogenesis of diabetes mellitus, besides being related to environmental and dietary factors, also clearly contains a genetic or familial component. Although the precise statistics supporting this statement vary with their source, it is estimated that between 25 and 50% of diabetic patients have “family histories” consistent with a genetic component. The reported incidence of diabetes is much higher in children derived from parents who both have diabetes. Also, monozygotic (identical) twins have a significantly higher incidence of diabetes than dizygotic (fraternal) twins. Current evidence favors the position that the inheritance is polygenic or multifactorial; in some specific instances there is clear evidence of a recessive gene for diabetes.
The Pima Indians have an incidence rate of diabetes that approaches 50% or higher. Also, there are animal models of diabetes (the Ob/Ob and Db/Db diabetic mouse and the Zucker rat) that clearly reflect genetic transmission.
4. Glucagon Diseases
In contrast to the situation relating to insulin, there are relatively few disease states that can be specifically ascribed to dysfunctions of glucagon. The syndrome of hyperglucagonemia was only first described in 1966. This condition arises as a consequence of the presence of a glucagon-secreting tumor of the pancreatic α-cell. This results in a detectable mass in the pancreas, anemia, and the presence of a blistering rash of the but tocks, abdomen, and groin area.
